autoimmune hepatitis or drug induced liver injury
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Autoimmune Hepatitis or Drug Induced Liver Injury
Keith D. Lindor, M.D. Arizona State University
PresenterPresentation NotesThank you. Well, it's very nice to be here. My focus today is going to be trying to help, looking at a patient's perspective, using a clinician's viewpoint, how we might differentiate a drug-induced liver injury from autoimmune hepatitis. As Chris said, this is not an easy task.What I thought I'd do in this talk is first talk about autoimmune hepatitis, give you some background, some views of what it looks like as a clinical presentation, and then briefly talk about drug-induced liver injury, and show you really how difficult it can be to distinguish between the two, both on clinical, serologic and typical liver biochemical grounds. And then talk about the histology, and it is is largely drawn from a paper that we published last September, looking at histologic features of drug-induced liver injury versus autoimmune hepatitis.
AUTOIMMUNE HEPATITIS 100,000 200,000 persons in USA Female>Male, all ages, occurs worldwide
PresenterPresentation NotesAutoimmune hepatitis is probably not quite as common as this slide says. We usually think in terms of 100 per million. So this would be somewhere around half as common as this would represent. It occurs more often in women than men, and it occurs really in all ages.
Unknown usually no trigger identified Viruses, drugs (minocycline) and herbal
preparations can trigger Disease can persist despite withdrawal of
trigger ? Molecular mimicry between foreign and self
antigens Associated with other AI diseases
PresenterPresentation NotesWe don't know what causes autoimmune hepatitis. Something seems to trigger it in many cases. It could be a virus, a drug, herbal preparation. We oftentimes don't know. There's probably a genetic predisposition. HLA phenotyping helps us with this. One of the challenges has been that there can be what seems like an acute event, and then a long-lasting autoimmune process seems to occur. There may be -- part of this may be molecular mimicry between the inciting antigen and pieces of the liver in which the immune response then is perpetuated against. There is a strong association of autoimmune hepatitis with other autoimmune kinds of disease. I think helping suggest that there may be this genetic predisposition to an autoimmune process that becomes self-perpetuating and won't shut off.
AUTOIMMUNE HEPATITIS Disease Spectrum
Classical chronic hepatitis + cirrhosis Burned-out cirrhosis Acute hepatitis Fulminant hepatitis Overlap syndrome with PSC or PBC
PresenterPresentation NotesThe presentation for autoimmune hepatitis can be very varied. It can range from cirrhosis and patients recovering from liver transplantation, to a very mild, burnt out cirrhosis, which is oftentimes only discovered incidentally at the time of imaging or other testing. It could present acutely in about 20 percent or so of patients with autoimmune hepatitis having acute presentation. It can be fulminant. These patients can look like they're going to die if they don't require a transplant or steroid therapy. They may be deeply jaundiced. It could also be confused with other chronic liver diseases, such as primary biliary sclerosis or primary sclerosing cholangitis.
AUTOIMMUNE HEPATITIS Diagnosis
International AIH scoring system Complicated
Histologic hallmark is interface hepatitis, but not specific Hypergammaglobulinemia and autoantibodies No cholestatic features No drug or viral cause, alcohol limit 25 g/d
Alvarez F, et al. J Hepatol 1999;31:929-38; Hennes EM, et al. Hepatology 2008;48:169-76
PresenterPresentation NotesSo it's not a neat diagnostic category in and of itself, when we as clinicians see patients with this problem. There have been a variety of scoring systems that have been used to try and help identify these patients. These scoring systems are often useful in categorizing patients when we look at combined series. But their application amongst individuals with the disease is sometimes troublesome. So useful for broad categorization, but as clinical tools for individual diagnosis, they leave quite a bit to be desired.
Interface Hepatitis Lympho-Plasmacytic
infiltrate Interface hepatitis Lympho-Plasmacytic
PresenterPresentation NotesAll of the diagnoses for autoimmune hepatitis rely on histology. Primary biliary sclerosis, primary sclerosing cholangitis, hemochromatosis. We've moved away from in many chronic liver diseases from requiring a liver biopsy. Autoimmune hepatitis requires a liver biopsy for its diagnosis. These patients have evidence of a heightened immune response, with elevated gammaglobulin levels and auto-antibodies. They typically don't have cholestatic features. Some may have some bile duct injury, but that's not the typical feature, and usually we can't find a specific cause, including excess alcohol use. The characteristic histologic features, that of interface hepatitis. Interface hepatitis, when we think of the liver, we think of portal spaces where the vessels and the bile ducts flow, and then the liver parenchyma, where the hepatocytes reside. That limitation is called the limiting plate. If I was going to use this room as a model for the liver, I would probably call the tables the portal tracks, and the spaces in between the hepatocytes. So the edges of the table would be the limiting plate. So interface hepatitis is inflammation that extends from the portal space into the hepatic parenchyma, and that's characteristic of autoimmune hepatitis. But it also characterizes Stage 2 PBC, Stage 2 PSC, and so it isn't unique to this disease. Also, the types of cells that we see, we heard some of this discussion earlier in some of the models, is lymphocytoplasmic. It's not usually neutrophils; it's more of a chronic inflammatory condition, but again not unique. So the histologic features are suggested, but they're not unique to making this diagnosis.
AUTOIMMUNE HEPATITIS Clinical Features
Patients, % Clinical features female 70 < 40 yrs old 50 acute onset 40 fatigue 85 jaundice 46 myalgias 30 hepatomegaly 78
PresenterPresentation NotesNow there are a variety of other clinical features that can help, but these are again fairly non-specific: muscle aches, large liver, tiredness are suggestive, but clearly don't make the diagnosis.
AUTOIMMUNE HEPATITIS Subtypes
Type 1 Type 2
Characteristic autoAbs 75%ANA, SMA anti-LKM1
Associated autoAbs pANCA,SLA/LP anti-LC-1
Age at onset all ages 2-14 yrs
Associated diseases thyroiditis UC synovitis
vitiligo type 1 diabetes
Treatment steroids steroids
Tx failure uncommon common
PresenterPresentation NotesWe do look at auto-antibodies. These could be helpful, and some who have been more interested in splitting different types have split one type that's uncommon in adults, LKM-1 Type 2 autoimmune hepatitis. Two to three percent maybe of the adult population have this. It's more common in children. LKM antibody characterizes this. Most people with autoimmune hepatitis have auto-nuclear or anti-nuclear antibodies or anti-smooth muscle antibodies. But again, this can be seen in drug-induced liver injury. They can have a variety of other associated diseases. I mentioned the autoimmune diseases. Thyroiditis is probably the most common of these, ulcerative colitis and a few diabetes and less. Fortunately autoimmune hepatitis has a treatment. It's cortical steroids with or without azathioprine, and this is effective in most people.
AUTOIMMUNE HEPATITIS Genetic Predispositions
HLA-DR3 and HLA-DR4 present in most Caucasian North American and Northern European patients with type 1 autoimmune hepatitis
HLA-DR3 (DRB1*0301) associated with early-age onset, more treatment failure and frequent need for liver transplantation
HLA-DR4 (DRB1*401) associated with a good treatment result, older patients, and frequent concurrent immune diseases
PresenterPresentation NotesI mentioned the genetic background. These are some of the HLA associations that have been made with autoimmune hepatitis. Some are associated with earlier onset, more severe disease, whereas others, HLA-DR4, seem to be associated with a less severe course of the disease.
Czaja A. Atlas Liver Disease 2005
PresenterPresentation NotesSo a little prognostic information, but again, diagnostically these have not been that helpful. Now the natural history, you may have trouble seeing this slide, really ranges from initial portal hypertension all the way through increased fibrosis to cirrhosis, which isolates the normal parts of the liver leading to portal hypertension, and possibly end stage liver disease. So there can be a broad spectrum of ways that this disease presents. Many times we see patients early on in the course of the disease.
INDICATIONS FOR THERAPY Defined Not well defined
AST > 10 times ULN Mild disease
AST > 5 times ULN + IgG > 2 times ULN
Severe fulminant disease
Bridging or multilobular necrosis
Seronegative chronic hepatitis
Relative symptoms, interface hepatitis, AST lower than absolute criteria
Asymptomatic patients may not required therapy
Feld JJ, et al; Hepatology 2005;42:53-62
PresenterPresentation NotesIf they're effectively treated, they may have a normal life expectancy. If they aren't effectively treated, they will go on, in many cases, to develop cirrhosis and the need for liver transplantati